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Controlling protein function by fine-tuning conformational flexibility

In a living cell, protein function is regulated in several ways, including post-translational modifications (PTMs), protein-protein interaction, or by the global environment (e.g. crowding or phase separation). While site-specific PTMs act very locally on the protein, specific protein interactions t...

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Detalles Bibliográficos
Autores principales: Schmid, Sonja, Hugel, Thorsten
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375816/
https://www.ncbi.nlm.nih.gov/pubmed/32697684
http://dx.doi.org/10.7554/eLife.57180
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author Schmid, Sonja
Hugel, Thorsten
author_facet Schmid, Sonja
Hugel, Thorsten
author_sort Schmid, Sonja
collection PubMed
description In a living cell, protein function is regulated in several ways, including post-translational modifications (PTMs), protein-protein interaction, or by the global environment (e.g. crowding or phase separation). While site-specific PTMs act very locally on the protein, specific protein interactions typically affect larger (sub-)domains, and global changes affect the whole protein non-specifically. Herein, we directly observe protein regulation under three different degrees of localization, and present the effects on the Hsp90 chaperone system at the levels of conformational steady states, kinetics and protein function. Interestingly using single-molecule FRET, we find that similar functional and conformational steady states are caused by completely different underlying kinetics. We disentangle specific and non-specific effects that control Hsp90’s ATPase function, which has remained a puzzle up to now. Lastly, we introduce a new mechanistic concept: functional stimulation through conformational confinement. Our results demonstrate how cellular protein regulation works by fine-tuning the conformational state space of proteins.
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spelling pubmed-73758162020-07-24 Controlling protein function by fine-tuning conformational flexibility Schmid, Sonja Hugel, Thorsten eLife Biochemistry and Chemical Biology In a living cell, protein function is regulated in several ways, including post-translational modifications (PTMs), protein-protein interaction, or by the global environment (e.g. crowding or phase separation). While site-specific PTMs act very locally on the protein, specific protein interactions typically affect larger (sub-)domains, and global changes affect the whole protein non-specifically. Herein, we directly observe protein regulation under three different degrees of localization, and present the effects on the Hsp90 chaperone system at the levels of conformational steady states, kinetics and protein function. Interestingly using single-molecule FRET, we find that similar functional and conformational steady states are caused by completely different underlying kinetics. We disentangle specific and non-specific effects that control Hsp90’s ATPase function, which has remained a puzzle up to now. Lastly, we introduce a new mechanistic concept: functional stimulation through conformational confinement. Our results demonstrate how cellular protein regulation works by fine-tuning the conformational state space of proteins. eLife Sciences Publications, Ltd 2020-07-22 /pmc/articles/PMC7375816/ /pubmed/32697684 http://dx.doi.org/10.7554/eLife.57180 Text en © 2020, Schmid and Hugel http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Schmid, Sonja
Hugel, Thorsten
Controlling protein function by fine-tuning conformational flexibility
title Controlling protein function by fine-tuning conformational flexibility
title_full Controlling protein function by fine-tuning conformational flexibility
title_fullStr Controlling protein function by fine-tuning conformational flexibility
title_full_unstemmed Controlling protein function by fine-tuning conformational flexibility
title_short Controlling protein function by fine-tuning conformational flexibility
title_sort controlling protein function by fine-tuning conformational flexibility
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375816/
https://www.ncbi.nlm.nih.gov/pubmed/32697684
http://dx.doi.org/10.7554/eLife.57180
work_keys_str_mv AT schmidsonja controllingproteinfunctionbyfinetuningconformationalflexibility
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